| Literature DB >> 32111619 |
Yasuhiro Yamazaki1, Raul Urrutia2, Luis M Franco3, Silvia Giliani4,5, Kejian Zhang6,7, Anas M Alazami8,9, A Kerry Dobbs1, Stefania Masneri4,5, Avni Joshi10, Francisco Otaizo-Carrasquero11, Timothy G Myers11, Sundar Ganesan12, Maria Pia Bondioni13, Mai Lan Ho14, Catherine Marks14, Huda Alajlan8, Reem W Mohammed15, Fanggeng Zou7,16, C Alexander Valencia7,17,18,19, Alexandra H Filipovich20, Fabio Facchetti4, Bertrand Boisson21,22,23, Chiara Azzari24,25, Bander K Al-Saud15,26, Hamoud Al-Mousa15,26, Jean Laurent Casanova21,22,23,27,28, Roshini S Abraham29,30, Luigi D Notarangelo31.
Abstract
We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.Entities:
Mesh：
Substances：
Year: 2020 PMID： 32111619 PMCID： PMC7189207 DOI： 10.1126/sciimmunol.aax1036
Source DB: PubMed Journal: Sci Immunol ISSN： 2470-9468